PROJECT SUMMARY There is an urgent need to develop effective strategies to combat impaired memory and cognitive decline in Alzheimer?s disease (AD), but there is a serious lack of validated drug targets. Members of our team recently demonstrated that the transcription factor DFosB accumulates to very high levels in the hippocampus, a brain region critical for learning, in AD patients and AD mouse models. DFosB regulates the expression of genes crucial for memory and learning, and its overexpression in the hippocampus drives cognitive deficits. We recently demonstrated that DFosB binds DNA under control of a redox switch in vitro, but it is not known exactly how the redox switch in DFosB impacts its ability to bind to DNA at the promoters of genes to regulate their expression in vivo. Further, though we know that AD generates tremendous oxidative stress in the brain, it is unknown whether compounds targeting DFosB and/or its redox switch would protect against cognitive decline in AD. We do know that DFosB has a well-described role in drug addiction, accumulating in another brain region, the nucleus accumbens, where it mediates the rewarding effects of drugs of abuse by regulating the expression of many genes crucial to drug addiction. Through our parent grant we are developing chemical probes to investigate the mechanism of DFosB in vivo and validate DFosB as a potential drug target to treat drug addiction. However, our new findings suggest that DFosB can also be leveraged to counter cognitive decline in AD patients or leveraged as a biomarker to diagnose and/or predict early onset AD. We hypothesize that the redox switch within DFosB is a key molecular feature that controls its ability to regulate genes and that blocking DFosB by targeting its redox switch would protect against cognitive decline in AD. Building on our current success in identifying compounds that target DFosB, we propose in this Administrative Supplement to generate compounds and animal models to validate DFosB as a biomarker and therapeutic target for AD. Our approach is to 1) pharmacologically block DFosB in AD mice using our existing chemical scaffolds to see if they prevent or reverse cognitive decline; 2) genetically target the redox switch in DFosB in AD mice through viral vectors and transgenic tools to assess if it affects cognitive decline; and 3) generate a panel of novel compounds that selectively target the redox switch of DFosB. To this end, we have already in place a very strong, translational research platform that draws on our prior work using animal models of cognition, an AD mouse model, biochemical assays, medicinal chemistry, and structural biology. Thus, the positive impact will be the creation of tools to determine whether DFosB can be leveraged to oppose cognitive impairment in AD. This proposal is innovative because it develops new animal models and chemical probes that will be a critical milestone on the path towards developing molecules that target DFosB as novel therapeutics or diagnostics for cognitive decline in AD.